Statin in combination with cisplatin makes favorable tumor-immune microenvironment for immunotherapy of head and neck squamous cell carcinoma

Abstract

Background: Immune checkpoint inhibitors (ICIs) targeting programmed cell death 1 receptor (PD-1) or its ligand (PD-L1) improved survival in patients with advanced head and neck squamous cell carcinoma (HNSCC), and approval for its use was granted by the Food Drug Administration in the USA. However, anti-PD-1 antibodies did not significantly affect the progression-free survival rate of patients with HNSCC. Consequently, new approaches to improve treatment efficacy through the combination of conventional therapies and ICIs for the treatment of HNSCC are being investigated. The purpose of this study was to determine whether statins can enhance anticancer effects in HNSCC when used with cisplatin and act as immunogenic cell death (ICD) inducers that can be used in cancer immunotherapy.

Material and methods: In this study, we sought to determine whether statin use could lead to synergistic antitumor effects with cisplatin against HNSCC by analyzing data from a hospital cohort of patients who had received cisplatin-based induction chemotherapy (IC). We then reconfirmed the anticancer effect of statins in an experimental setting in relation to ICD mechanisms. Finally, we sought to determine the combined effect of cisplatin and statins against HNSCC and validate whether the combination enhanced anticancer immune responses, possibly leading to further synergistic effects if used in triple combination with ICIs.

Results: The pre-diagnosis use of statins in patients with HNSCC who underwent cisplatin-based IC was significantly associated with improved overall survival. Statins alone showed both in vitro and in vivo inhibitory effects against HNSCC, and synergistic antitumor effects were observed when combined with cisplatin in a syngeneic murine HNSCC model. Statins increased calreticulin exposure and endoplasmic reticulum stress-related signals in HNSCC cells. In addition, it was confirmed that statins could activate antigen-presenting cells and tumor-specific CD8+ T cells with an increase in their numbers in the tumor tissues and draining lymph nodes, with this effect showing significant improvement following the combination therapy with cisplatin. Moreover, in triple combination with both cisplatin and anti-programmed cell death 1 receptor (anti-PD-1) antibody, statins dramatically induced further tumor eradication and improved the survival of tumor-bearing mice.

Conclusions: Taken together, these results demonstrate that statins, administered in combination with anti-PD-1 antibody, could enhance the anticancer effect of cisplatin and potentiate the efficacy of immunotherapy for HNSCC and present a rationale for repurposing statins as an adjuvant immunotherapeutic option for HNSCC.